This is a request for a renewal of a collaborative program of basic and clinical research into the neurobiologic basic of major psychiatric disorders. A coordinated, interactive and multidiscriplinary program of research if focused on the neurolgiology of psychosis, depression, and anxiety disorders, and the mechanism of action of drugs used in their treatment. A collaborative team of preclinical and clinical research scientists conduct studies at the molecular, biochemical, anatomical, neurophysiological, behavioral and clinical levels. The programmatic interaction between basic and clinical research scientists over the 22 years of prior support has resulted in several major discoveries of the mechanism of action of psychotropic drugs, the development of neurotransmitter receptor ~challenge tests~ for the neurobiologic evaluation of patients, and the discovery of new treatments for opiate withdrawal and depression. In Project I, the initial findings that antipsychotic drugs regulate glutamate receptors will be followed up with moleculas, biochemical and electrophysiologic studies focused on the pharmacologic characterization, anatomic specificity, and molecular mechanisms involved. Project 2 will evaluate our initial important finding that antidepressant treatments increase the function and expression of the cAMP response element binding protein (CRED) and brain derived neurtrophic factor (BDNF). The role of CREB in mediating the induction of BDNF and the functional consequences of increased expression of BDNF will be determined by a combination of molecular, cellular, and electrophysiological techniques. In Project 3 the role of the amygdala, hippocampus and the bed nucleus of the stria terminalis will be evaluated relative to two forms of anxiety (explicit cue and context conditioning). Drugs effecting the noradrenergic and serotonergic systems will be studied on these 2 measures of anxiety and this work will be extended into studies of patients with post-traumatic stress disorder. The projects will be supported transgenic mouse core facilities. Over the past 5 years this program has now evolved into the current proposal where all three of the projects utilize molecular methods and received essential support from the transgenic mouse core facility. Since the program previously successfully applied basic research findings to the study of patients, it is expected, that over the grant period, the ongoing basic molecular research will generate new clinical studies.